Matrix Metalloproteinase-8 and the Regulation of Blood Pressure, Vascular Inflammation, and Atherosclerotic Lesion Growth

See related articles, pages 921–929 The description in the early 1990s of intriguing associations between the expression/activity of specific matrix metalloproteinases (MMPs) and signs of plaque inflammation and matrix degradation1–3 spurred an impressive effort of research to precisely define the roles of MMPs in both the development and complications of atherosclerosis. After two decades of research in this area, mechanistic studies using genetically manipulated mice with deletion or overexpression of specific MMPs, complemented with genetic epidemiological studies, have revealed more complex and, sometimes divergent, roles of MMPs in the modulation of lesion development, progression and complications.4 There are many potential explanations for these findings. Ambivalent effects of specific MMPs have been reported in different models of atherosclerosis,5 emphasizing the urgent need for clinically relevant animal models of disease complications. For example, even the use of the brachiocephalic artery of apolipoprotein (Apo)E knockout mice as a model of site-specific plaque rupture did not allow to differentiate between the roles of MMPs in plaque development versus plaque complications. A close look at this model reveals that the number of buried fibrous caps is highly proportional to lesion size, independently of mouse genetic background and MMP expression.6 The complex role of MMPs in atherosclerosis could be attributed to the diversity of biological processes relevant to this disease, which are subject to tight control by MMPs and the modulation of which could have divergent consequences for lesion development and fibrous cap stability. The MMP-controlled processes include those classically related to matrix remodeling, vascular …